Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germline-inactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers are not known. To address these questions experimentally, we generated a Bap1+/− knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1+/− mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than wild-type (WT) littermates (73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1+/− mice than in WT animals (median survival, 43 weeks vs. 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1+/− mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1+/− mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in WT mice, mesotheliomas from Bap1+/− mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1+/− mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1+/− mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure. Cancer Res; 74(16); 1–10. ©2014 AACR.

The LITTLE Team for a CURE. From left: Patrick Heringslack, Tasha Little, Howard Little.

Tasha Little was 42 years old when she learned she had breast cancer. She had no family history of breast cancer, exercised regularly, maintained a healthy diet, and was active with her two boys. But, she still found herself facing a cancer diagnosis.

“I’ve always believed in preventative care,” says Tasha. “When I learned the lump that showed up on a routine mammogram was breast cancer, I was completely overwhelmed.”

At the time she was diagnosed, she had just gone through a divorce, and found out she had cancer while moving from her home of 13 years following the split.

Fortunately, Tasha had time to research her options. She decided to get her cancer treatment at the Abramson Cancer Center.

“Getting the cancer out of my body was obviously important to me,” she says, “but so was reconstruction. When I met Drs. Tchou and Wu, I knew I was in the right place.”

Tasha was impressed with the way both the surgical oncologist and plastic surgeon collaborated as a team.

“My surgeons had a wonderful relationship with each other, and it made me feel comfortable to know they worked together so well,” she says.

Tasha had unilateral mastectomy (removal of one breast) and reconstruction at Penn. That was just over a year ago, and today, she’s giving back by participating in the inaugural Philadelphia Ride to Conquer Cancer® that benefits the Abramson Cancer Center.

“I heard the radio ads, and since I was an avid cyclist before I was diagnosed, I thought it would be a great way for me to get back in the saddle for a good cause,” says Tasha.

Tasha invited her dad, Howard, and her friend Patrick to join her on the ride. Riding with her dad has been a special experience, because her family had a big part in her recovery.

“I was raising two boys. My mother would take me to the hospital while my dad stayed at home and took care of the boys,” says Tasha. “This whole experience was a family effort, even though it was something I personally dealt with.”

“Parents who know what it is like to have a sick child know that no words can comfort the fear and anxiety and emotions you experience as a parent,” says Howard. “Even with a child in her 40s, it still feels like she’s your little baby and you just want to comfort and protect her. You have to have hope and positivity and know that doctors are doing as much as they can for you.”

So far, “The LITTLE Team for a CURE has raised $4,811.00 and plans to meet their goal of $8,000.00 in time for the ride. “If you’re an avid rider, it’s about what you can do to help. If you’ve never rode before, it can be done. People are generous and if you’re passionate people will support you,” says Tasha.

The Ride to Conquer Cancer®

Join Penn Medicine’s Abramson Cancer Center (ACC) on October 11 to 12, 2014 in the Ride to Conquer Cancer (RTCC)—an unforgettable and epic bike ride through Pennsylvania’s picturesque landscape -towards one life-changing destination: to cure cancer. The ride isn’t just for cyclists, it’s for anyone who wants to see a cure for cancer.

At two-days and 150+ miles the RTCC will be a physical challenge—and an emotional and inspirational weekend—that will give you a chance to ride side by side with physicians, patients and families–raising serious funds and awareness in the ACC’s fight to cure cancer.

The funds raised through the ride will be put to use immediately, powering the ACC’s vision to eradicate cancer as a cause of human disease and suffering through precision medicine, novel research, next-generation therapies, and compassionate care.

Join Today

This event will be remarkable, bringing together communities of cancer survivors, cyclists, and their supporters with a common goal to conquer this disease. Join the ride in October by registering today at www.ridetovictory.org or by calling (844) 777-7433.

Before the ride, you will have access to:

• Expert coaching
• Training rides in your area
• Personal web page for fundraising
• Helpful manual
• 2014 ride commemorative item

During the ride, participants will have access to:

• Event-day ride jersey
• Support along the route
• Catered meals
• Entertainment at camp
• Massage and medical care

Hepatocellular carcinoma (HCC) was thought historically to arise from hepatocytes, but gene expression studies have suggested that it can also arise from fetal progenitor cells or their adult progenitor progeny. Here, we report the identification of a unique population of fetal liver progenitor cells in mice that can serve as a cell of origin in HCC development. In the transgenic model used, mice carry the Cited1-CreERTM-GFP BAC transgene in which a tamoxifen-inducible Cre (CreERTM) and GFP are controlled by a 190-kb 5′ genomic region of Cited1, a transcriptional coactivator protein for CBP/p300. Wnt signaling is critical for regulating self-renewal of progenitor/stem cells and has been implicated in the etiology of cancers of rapidly self-renewing tissues, so we hypothesized that Wnt pathway activation in CreERTM-GFP+ progenitors would result in HCC. In livers from the mouse model, transgene-expressing cells represented 4% of liver cells at E11.5 when other markers were expressed, characteristic of the hepatic stem/progenitor cells that give rise to adult hepatocytes, cholangiocytes, and SOX9+ periductal cells. By 26 weeks of age, more than 90% of Cited1-CreERTM-GFP;Ctnnb1ex3(fl) mice with Wnt pathway activation developed HCC and, in some cases, hepatoblastomas and lung metastases. HCC and hepatoblastomas resembled their human counterparts histologically, showing activation of Wnt, Ras/Raf/MAPK, and PI3K/AKT/mTOR pathways and expressing relevant stem/progenitor cell markers. Our results show that Wnt pathway activation is sufficient for malignant transformation of these unique liver progenitor cells, offering functional support for a fetal/adult progenitor origin of some human HCC. We believe this model may offer a valuable new tool to improve understanding of the cellular etiology and biology of HCC and hepatoblastomas and the development of improved therapeutics for these diseases. Cancer Res; 74(16); 1–11. ©2014 AACR.

Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IG) has proved instrumental in dissecting chronic lymphocytic leukemia (CLL) pathogenesis. Initially, it was the finding that the level of somatic hypermutations in rearranged IG heavy-chain genes could define two CLL subtypes associated with a different clinical course that drew attention. As the years ensued, this not only continued to hold strong, but also revealed an unprecedented BcR restriction (aptly coined as “stereotypy”), thus cementing the idea that antigenic elements select the leukemic clones. With all this in mind, in the present review, we focus on the CLL BcR IG, a molecule that clearly lies at the heart of disease pathogenesis, and attempt to distil from past and emerging biologic knowledge the most relevant aspects in the context of the immunogenetics of CLL, while at the same time provoking questions that remain unanswered. We juxtapose CLL with mutated BcR IGs against CLL with unmutated BcR IGs due to their striking clinicobiologic differences; however, when considering ontogeny, common derivation of the two mutational subtypes cannot be excluded. The issue of stereotypy is intertwined throughout and we also raise the subject of isotype-switched CLL, which, despite its rarity, contributes intriguing ontogenetic hints. Cancer Res; 74(16); 1–6. ©2014 AACR.

Distinct cytotoxic agents currently used in the oncological armamentarium mediate their clinical benefit by influencing, directly or indirectly, the immune system in such a way that innate and adaptive immunity contributes to the tumoricidal activity. Now, we bring up evidence that both arms of anticancer immunity can be triggered through the intervention of the intestinal microbiota. Alkylating agents, such as cyclophosphamide, set up the stage for enhanced permeability of the small intestine, facilitating the translocation of selected arrays of Gram-positive bacteria against which the host mounts effector pTh17 cells and memory Th1 responses. In addition, gut commensals, through lipopolysaccharide and other bacterial components, switch the tumor microenvironment, in particular the redox equilibrium and the TNF production of intratumoral myeloid cells during therapies with platinum salts or intratumoral TLR9 agonists combined with systemic anti-IL10R Ab respectively. Consequently, antibiotics can compromise the efficacy of certain chemotherapeutic or immunomodulatory regimens. Cancer Res; 74(16); 1–5. ©2014 AACR.